Vaccines, including respiratory syncytial virus (RSV) vaccines, are thermolabile and to overcome the instability barrier, are typically stored in a dried state. The labile nature of vaccines renders drying of vaccines a challenging task and often requires long conservative freeze-drying cycles (typically cycle times in excess 48-72 hours) to obtain dried thermostable vaccines. The thermolabile nature of the RSV (poor drying yield and stability) renders the virus susceptible to inactivation by minimal changes in the environment associated with drying and/or incubation at elevated temperatures. Historical approaches to obtain dried vaccine and biologics hinges mostly on the use of lyophilization and to a limited extent on spray-drying. However, vaccines, even if dried using these methods, have thus far failed to achieve adequate accelerated 37° C. and long-term room temperature stability.
Lyophilization processes typically entail freezing the vaccine components and then drying by sublimation. Methods of lyophilizing biological materials have been described. In these methods, liquid is formulated and filled into a primary container (mostly glass vials), freezing using a blast freezer and lyophilizing using the conventional freeze-drying approach. Techniques for obtaining frozen, discrete beads of material (vaccine, biologics, small molecules etc.) wherein individual samples of the biological material are frozen in bead form and dried prior to placing a desired number of the dried beads into a storage container such as a glass vial have been described. See International Patent Application Publication No. WO2013/066769. Historically, these methods relied on either (a) dispensing an aliquot of a liquid composition containing the desired amount of a biological material into a container of a cryogen such as liquid nitrogen, which results in direct contact of the biological material with the cryogen and/or (b) dispensing an aliquot of a liquid composition containing the biological material into a cavity present on a chilled solid plate, where the cavity contains the aliquot until it is frozen. RSV strains are particularly difficult to freeze-dry. See, e.g., Tannock et al., 1987, J. Clin. Microbiol. 25:1769-1771.
RSV vaccines are often stored at sub-zero temperatures in the presence of high concentrations of stabilizing sugars. See, e.g., Gupta et al., 1996, Vaccine 14:1417-20. Findings suggest that RSV stability was maintained best at sucrose concentrations >30% at sub-zero temperatures with greatest stability observed at −70° C. See Law et. al., 1968, Experimental biology and Medicine 128: 515-518. Similarly, other findings revealed that stabilization of RSV at sub-zero temperature conditions in the presence of sugars (25% sucrose or 10% trehalose or 10% sorbitol) effectively maintains stability. See e.g., Gupta et al., 1996, Vaccine 14:1417-20.
U.S. Pat. No. 5,565,318 describes the use of a polymeric sugar as a protective agent in the formation of room temperature stable semi-spheres containing biologically active materials. U.S. Patent Application Publication No. 20100297231 describes foam-forming formulations comprising a biologically active protein and a polyol. U.S. Patent Application Publication No. 20110243988 describes the use of polyols as a stabilizer for dry powder live virus vaccines.
Microwave vacuum-drying (MVD) is a rapid method that can yield products, such as foods, plants and biological materials, with improved stability compared to air-dried and freeze-dried products. Because the drying is done under reduced pressure, the boiling point of water and the oxygen content of the atmosphere is lowered, so food or medicinal components sensitive to oxidation and thermal degradation can be retained to a higher degree than by air-drying. See, e.g., U.S. Pat. Nos. 4,389,794; 4,664,924; 4,809,596; 4,882,851; 6,128,321; 6,956,865; and International Patent Application Publication Nos. WO 02/103407; WO 2009/033285; WO 2009/049409; and WO2013/010257.
Seo et al., 2004, Journal of Non-Crystalline Solids, 333:111-114 discloses a method for making sugar glass without caramelization of the sugar through the use of microwaves. International Patent Application No. PCT/EP2013/064422 describes methods of producing medicinal products by freeze-drying compositions comprising 20%-60% w/w of a non-polymeric sugar.
There is a desire for increased heat stability, especially for the developing world where transport, storage, and administration costs (mainly due to the need of continuous refrigeration, also referred to as the “cold chain”) represent a significant portion of the product cost.